CN107569514A

CN107569514A - It is a kind of to target the activated complex for improving p53 expression of tumor suppressor gene

Info

Publication number: CN107569514A
Application number: CN201710914788.0A
Authority: CN
Inventors: 乌林奇
Original assignee: Shenzhen Targeted Gene Technology Co Ltd
Current assignee: Shenzhen Targeted Gene Technology Co Ltd
Priority date: 2017-09-30
Filing date: 2017-09-30
Publication date: 2018-01-12

Abstract

The present invention relates to a kind of activated complex for targetting raising p53 expression of tumor suppressor gene, the activated complex is chelated by the raw material including following components and obtained：Anthocyanin and metal ion；The metal ion includes Fe²⁺、Ca²⁺、Zn²⁺、Se²⁺、Mg²⁺、Mn²⁺、Mo²⁺、K⁺、Rb⁺And Li⁺.Harmful free radicals are eliminated from anthocyanin, the several kinds of mineral elements ion of participation enzymic catalytic reaction and vitamin confactor (Cofacter (s)), P53 action target matrix metalloproteinases MMP, hypoxia inducible factor HIF, MDM2 zinc finger protein (structure is easily distorted by heavy metal ion), miRNA nickases Dicer regulation and control are started with, " enclosing target " (Encircle Target) regulation is carried out to P53 genes, reach control cancer cell development, induce cancer cell aging and death.

Description

It is a kind of to target the activated complex for improving p53 expression of tumor suppressor gene

Technical field

The present invention relates to targeting to press down cancer drug technical field, and in particular to a kind of target improves p53 expression of tumor suppressor gene Activated complex.

Background technology

Cancer is a kind of genopathy, is under the effect of outer environmental factor, is activated in human body cell in a variety of preceding oncogenes With the process of the multistage long term evolution of tumor suppressor gene inactivation.Before accurate medical technology maturation, the primary treatment hand of cancer Section is radiotherapy, chemotherapy and operation, although this three big treatment means of physicians' constantly improve, many cancer patients are still difficult to Cured.One of major reason is that the microenvironment of gene mutation is not intervened at all.With gene sequencing technology Maturation, particularly enzymatic activity control, the sharpening of DNA biochemical mechanisms, gene target intervention turn into precisely medical treatment important hair Open up direction.

According to《Science》A research that magazine in August, 2017 is delivered shows that the gene expression for having 17 kinds of cancers has very big It is overlapping.This means for some patients, their gene expression is possible to more be close to other kinds of cancer, Rather than the cancer suffered from itself.

P53 is a kind of tumor suppressor gene (Tumor suppressorgene), by the protein of this gene code (protein) it is a kind of transcription factor (transcriptional factor), which control the startup of cell cycle.P53 bases Because be find so far with human tumor correlation highest gene, it is p53 bases to cause tumour formation or the p53 albumen of cell transformation It is a kind of tumor promotion factor because of the product of mutation, it can eliminate normal p53 function.Malignant tumour more than 50% Patient (including liver cancer, breast cancer, carcinoma of urinary bladder, stomach cancer, colon cancer, prostate cancer, soft tissue sarcoma, oophoroma, brain tumor, lymph Cell tumour, cancer of the esophagus, lung cancer, osteogenic sarcoma etc.) mutation of p53 genes occurs in vivo.To this phase in each cancer kind of P53 Guan Xing, Duplication highest gene expression are effectively adjusted, and have certain directive significance for targeted therapy.

It is less for the drug research of p53 targeted therapies at present, for p53 genes still without a kind of effective, more site targets To the medicine of intervention.

The content of the invention

It is an object of the invention to provide a kind of activated complex for targetting raising p53 expression of tumor suppressor gene.

The invention provides it is a kind of target improve p53 expression of tumor suppressor gene activated complex, the activated complex by Raw material chelating including following components obtains：Anthocyanin and metal ion；The metal ion includes Fe²⁺、Ca²⁺、Zn²⁺、Se²⁺、 Mg²⁺、Mn²⁺、Mo²⁺、K⁺、Rb⁺And Li⁺In one or more.

Present invention also offers a kind of activated complex solution for targetting raising p53 expression of tumor suppressor gene, the activity is multiple The solvent of polymer solution is water, and solute includes anthocyanin and metal ion；The metal ion includes Fe²⁺、Ca²⁺、Zn²⁺、Se²⁺、 Mg²⁺、Mn²⁺、Mo²⁺、K⁺、Rb⁺And Li⁺In one or more.

Preferably, concentration of the anthocyanin in activated complex solution is 1~100mg/ml.

Preferably, the anthocyanin is plant extract anthocyanin, and the plant includes purple sweetpotato, grape, blood is orange, red ball is sweet One or more in indigo plant, blueberry, eggplant, cherry, the red certain kind of berries, strawberry, mulberries, hawthorn and morning glory.

Preferably, the mass content of anthocyanin is 3~50% in the plant extract anthocyanin.

Preferably, concentration of the metal ion in activated complex solution is as follows：Fe²⁺Concentration for 0.1~ 0.4mg/ml, Ca²⁺Concentration be 0.2~20mg/ml, Zn²⁺Concentration be 0.04~0.38mg/ml, Se²⁺Concentration be 0.0001~0.004mg/ml, Mg²⁺Concentration be 0.4~7mg/ml, Mn²⁺Concentration be 0.0004~0.06mg/ml, Mo²⁺'s Concentration is 0.0002~0.007mg/ml, K⁺Concentration be 0.4~112.5mg/ml, Rb⁺Concentration for 0.0004~ 0.0952mg/ml, Li⁺Concentration be 0.0004~0.012mg/ml.

Preferably, concentration of the metal ion in activated complex solution is as follows：Fe²⁺Concentration for 0.2~ 0.3mg/ml, Ca²⁺Concentration be 0.5~15mg/ml, Zn²⁺Concentration be 0.15~0.28mg/ml, Se²⁺Concentration be 0.0002~0.003mg/ml, Mg²⁺Concentration be 1.5~6mg/ml, Mn²⁺Concentration be 0.01~0.05mg/ml, Mo²⁺It is dense Spend for 0.0008~0.006mg/ml, K⁺Concentration be 5~100mg/ml, Rb⁺Concentration be 0.002~0.08mg/ml, Li⁺'s Concentration is 0.001~0.012mg/ml.

Preferably, the metal ion derives from the active ionic water purified with mineral matter.

Preferably, the metal ion derives from the plant extracts rich in metal ion, including Fe²⁺Extract, Ca²⁺ Extract, Zn²⁺Extract, Se²⁺Extract, Mg²⁺Extract, Mn²⁺Extract, Mo²⁺Extract, K⁺Extract, Rb⁺Extract And Li⁺Extract.

Preferably, the Fe²⁺Extract is cherry extract, the Ca²⁺Extract include mass ratio for (0.9~ 1.1)：(0.9~1.1) Thallus Laminariae (Thallus Eckloniae) extract and Herba Apii graveolentis extract；The Zn²⁺Extract includes mass ratio (0.9~1.1)：(0.9 ~1.1)：Abelmoschus Esculentus Linn extract, blueberry extract and the male silk moth extract of (0.9~1.1)；The Se²⁺Extract, Rb⁺Carry It is marine algae extract to take thing；The Mg²⁺Extract includes mass ratio (0.9~1.1)：(0.9~1.1)：The hazel of (0.9~1.1) Seed extract, Semen phaseoli radiati extract and thyme extract；The Mn²⁺Extract includes mass ratio (0.9~1.1)：(0.9~ 1.1) Echinacea Purpurea Herb P.E and green-tea extract；The Mo²⁺Extract is extract of soybean；The K⁺Extract includes quality Than (0.9~1.1)：(0.9~1.1)：(0.9~1.1)：Thallus Laminariae (Thallus Eckloniae) extract, banana extract, the dried peppermint leaf of (0.9~1.1) carry Take thing and wax gourd extract；The Li⁺Extract is to spread out numb tea extraction.

Beneficial effects of the present invention：The activated complex is obtained by being chelated by the raw material including following components：Anthocyanin And metal ion, the existence form of the chelate enable the metal ion in the activated complex to smoothly complete including wearing Microcirculation transport inside more including blood-brain barrier.The present invention starts with from the regulation and control of the following aspects, including：1) anthocyanin pair Harmful free radicals eliminate；2) the various metals ion and vitamin confactor (Cofacter (s)) of enzymic catalytic reaction are participated in；3) P53 action target matrix metalloproteinases MMP；4) hypoxia inducible factor HIF；5) (structure is easily by heavy metal for MDM2 zinc finger proteins Ion is distorted)；6) miRNA nickases Dicer, " enclosing target " (Encircle Target) regulation is carried out to P53 genes, reverses DNA Methylate and activate repressed p53 activity, increase and Time of Administration with anthocyanin and concentration of metal ions in tumour cell Increase, p53 protein expressions dramatically increase, and p53 gene methylation situations significantly reduce.Recorded according to embodiment, pass through three The clinical intervention validity check control of first hospital, after more than 65 patients take activated complex of the present invention, blood closes Key immune indexes, tumor markers index are obviously controlled or recover normal completely.

Embodiment

In the present invention, the anthocyanin is preferably derived from plant extracts, and the plant includes purple sweetpotato, grape, blood One or more in orange, red cabbage, blueberry, eggplant, cherry, the red certain kind of berries, strawberry, mulberries, hawthorn and morning glory.The present invention is right The extracting method of the anthocyanin is not particularly limited, using the technical scheme of the conventional extraction anthocyanin in this area. It is prepared by the commission of anthocyanin described in specific implementation process of the present invention Daxing'an Mountainrange Lin Gebei psychrophiles Science and Technology Co., Ltd. Obtain.The mass content of anthocyanin is preferably 3~50% in the plant extract anthocyanin in the present invention, more preferably 10~30%.

In the present invention, the concentration of anthocyanin is preferably 1~100mg/ml in the activated complex solution, more preferably For 2~60mg/ml, most preferably 3~10mg/ml.In the present invention, the anthocyanin act as：Supplied as hydroxyl Body, its phenol type structure make it have anti-oxidation function, by scavenging capacity chalcogen (ROS), such as oxygen radical (O^2-), singlet oxygen (O₂), peroxide (ROO-), hydrogen peroxide (H₂O₂) and hydroxy radical (OH^-) etc. oxidation reaction enliven intermediary's material, induction P53 is expressed.

In the present invention, anthocyanin is combined preferably as carrier with metal ion, forms chelate, the chelate Existence form enable the metal ion be smoothly rapidly completed including passing through blood-brain barrier inside microcirculation transport. The state of the chelate has no effect on the performance of the anthocyanin effect, and the sequestering properties are advantageous to by carrier of anthocyanin Promote metal ion fast transportation in vivo and absorption；After the metal ion is entered in vivo with chelate state, according to need Dissociated or recombined on anthocyanin accordingly.

In the present invention, the activated complex solution includes metal cations Fe²⁺, preferable described Fe²⁺From with Iron content mineral matter purification active ionic water or from rich in Fe²⁺Plant extracts, the mineral matter of the iron content carries Pure active ionic water preferably entrusts Qingdao Shen Dongkuang liquid Co., Ltd to prepare；The Fe²⁺Extract is cherry extract.This In activated complex solution described in invention, Fe²⁺Concentration is preferably 0.1~0.4mg/ml, more preferably 0.2~0.3mg/ ml.Heretofore described Fe²⁺It act as：Hemoglobin ferrous ion is supplemented, increase hemoglobin synthesis, activates the work of oxygenase Property, strengthen blood oxygen concentration；Suppression of the nearly and complementary enhancing p53 to hypoxia inducible factor HIF；The enhancing of oxonium ion, is also helped Maintained vigour in Ubiquitin-proteasome, HIF-l α subunits is kept reduced levels.

In the present invention, the activated complex solution includes metallic ions Ca²⁺, preferable described Ca²⁺From with Calcic mineral matter purification active ionic water or from rich in Ca²⁺Plant extracts, the Ca²⁺Extract is sea Band extract and Herba Apii graveolentis extract.The Ca²⁺The mass ratio of Thallus Laminariae (Thallus Eckloniae) extract and Herba Apii graveolentis extract is preferably in extract (0.9~1.1)：(0.9~1.1), more preferably 1:1；In heretofore described activated complex solution, Ca²⁺Concentration is preferred For 0.2~20mg/ml, more preferably 0.5~15mg/ml.Heretofore described Ca²⁺It act as：Fibrinolysin is activated with swashing Peptide discharges enzyme, and resolution improves fibrinolytic, reduces fiber protein content in blood plasma, reduces cancer embolus generation and tissue fibers wind transmission Danger.

In the present invention, the activated complex solution includes configuration metal ions Zn²⁺, preferable described Zn²⁺From with Containing zinc mineral matter purification active ionic water or from rich in Zn²⁺Plant extracts, the Zn²⁺Extract includes Abelmoschus Esculentus Linn extract, blueberry extract and male silk moth extract；The Abelmoschus Esculentus Linn extract, blueberry extract and male silk moth extraction The mass ratio (0.9~1.1) of thing：(0.9~1.1)：(0.9~1.1), more preferably 1:1:1.Heretofore described activity is multiple In polymer solution, Zn²⁺Concentration is preferably 0.04~0.38mg/ml, more preferably 0.15~0.28mg/ml.In the present invention The Zn²⁺It act as：Cd in zinc finger protein structure is distorted in displacement²⁺、Hg²⁺、Co²⁺、Cu²⁺, while suppress Metal Ions Cd²⁺、Hg² ⁺、Co²⁺、Cu²⁺Absorption and enzymatic reaction activity.

In the present invention, the activated complex solution includes metal ion Se²⁺, preferable described Se²⁺From with Containing selenium mineral matter purification active ionic water or from rich in Se²⁺Plant extracts, the Se²⁺Extract is sea Algae extract.In heretofore described activated complex solution, Se²⁺Concentration is preferably 0.0001~0.004mg/ml, more excellent Choosing for 0.0002~0.003mg/ml.Heretofore described Se²⁺As：Cd in zinc finger protein structure is distorted in displacement²⁺、Hg²⁺、 Co²⁺、Cu²⁺, while suppress Metal Ions Cd²⁺、Hg²⁺、Co²⁺、Cu²⁺Absorption and enzymatic reaction activity.

In the present invention, the activated complex solution includes metal ions M g²⁺, preferable described Mg²⁺From with Containing magnesium mineral matter purification active ionic water or from rich in Mg²⁺Plant extracts, the Mg²⁺Extract includes Hazel extract, Semen phaseoli radiati extract and thyme extract, the hazel extract, Semen phaseoli radiati extract and thyme extract Mass ratio is preferably (0.9~1.1)：(0.9~1.1)：(0.9~1.1), more preferably 1:1:1.Heretofore described work In property complex solution, Mg²⁺Concentration is preferably 0.4~7mg/ml, more preferably 1.5~6mg/ml.It is heretofore described Mg²⁺Effect includes the conservative amino acid residues site with reference to Dicer enzymatics center, Dicer is attached to dsRNA, triggers big The cutting mRNA reactions of amount, obtain miRNA precursors；The direct action target miRNA of p53, apoptosis-induced, aging and cell cycle stop It is stagnant.The Mg²⁺Effect also includes and Mn²⁺, K⁺And Rb⁺Collective effect activation pyruvate kinase (pyruvate kinase, PK), In glycolysis system, it is the enzyme that catalysis forms second ATP reaction.In ATP and Mg²⁺Under participation, fructose-1, 6-diphosphate kinases 1 (6-phosphofructokinase1, PFK1) in glycolytic pathway, catalysis fructose-1, 6-diphosphate generates fructose 1,6-diphosphate (Fructosel, 6bisphosphate, F-1,6-BP), accelerate second of phosphorylation reaction of glycolytic pathway, improve activity Oxygen content, make cancer cell that the mechanism of apoptosis occur.

In the present invention, the activated complex solution includes metal ions M n²⁺, preferable described Mn²⁺From with Containing manganese mineral matter purification active ionic water or from rich in Mn²⁺Plant extracts, the Mn²⁺Extract includes Echinacea Purpurea Herb P.E and green-tea extract, the mass ratio of the Echinacea Purpurea Herb P.E and green-tea extract be preferably (0.9~ 1.1)：(0.9~1.1), more preferably 1:1.In heretofore described activated complex solution, Mn²⁺Concentration is preferably 0.0004~0.06mg/ml, more preferably 0.01~0.05mg/ml.Heretofore described Mn²⁺Effect includes combining Dicer The conservative amino acid residues site at enzymatic center, Dicer is attached to dsRNA, trigger substantial amounts of cutting mRNA reactions, obtain MiRNA precursors；The direct action target miRNA of p53, apoptosis-induced, aging and cell cycle arrest.The Mn²⁺Effect also includes With Mg²⁺, K⁺And Rb⁺Collective effect activation pyruvate kinase (pyruvate kinase, PK), in glycolysis system, it is to urge Change the enzyme for forming second ATP reaction.Active o content is improved, makes cancer cell that the mechanism of apoptosis occur.The Mn²⁺Effect is also wrapped Include by supplementing Mn²⁺Intake, Intramitochondrial manganese is supplemented, increase hemoglobin synthesis, the activity of oxygenase is activated, strengthens blood oxygen Concentration；Suppression of the nearly and complementary enhancing p53 to hypoxia inducible factor HIF；The enhancing of oxonium ion, it helps ubiquitin protein enzyme Body maintains vigour, and HIF-l α subunits is kept reduced levels.

In the present invention, the activated complex solution includes metal ions M o²⁺, preferable described Mo²⁺From with Containing molybdenum mineral matter purification active ionic water or from rich in Mo²⁺Plant extracts, the Mo²⁺Extract is big Beans extract.In heretofore described activated complex solution, Mo²⁺Concentration is preferably 0.0002~0.007mg/ml, more excellent Choosing for 0.0008~0.006mg/ml.Heretofore described Mo²⁺Effect includes passing through Mo²⁺Balance and suppression Cu²⁺Activity and Absorb, suppress LOX to p53 hydroxylating, the Mo²⁺Effect also distorts Cd in zinc finger protein structure including displacement²⁺、Hg²⁺、Co² ⁺、Cu²⁺, while suppress Metal Ions Cd²⁺、Hg²⁺、Co²⁺、Cu²⁺Absorption and enzymatic reaction activity.

In the present invention, the activated complex solution includes metal ion K⁺, preferable described K⁺From with containing potassium Mineral matter purification active ionic water or from rich in K⁺Plant extracts, the K⁺Extract extracts including sea-tangle Thing, banana extract, peppermint leaf extract and wax gourd extract, the Thallus Laminariae (Thallus Eckloniae) extract, banana extract, peppermint leaf extract (0.9~1.1) is preferably with the mass ratio of wax gourd extract：(0.9~1.1)：(0.9~1.1)：(0.9~1.1), it is more excellent Choosing for 1:1：1:1.K in heretofore described activated complex solution⁺Concentration is preferably 0.4~112.5mg/ml, more excellent Choosing for 5~100mg/ml.Heretofore described K⁺It act as by supplementing K⁺、Li⁺And Ca²⁺Fibrinolysin is activated to discharge with kassinin kinin Enzyme, resolution improve fibrinolytic, reduce fiber protein content in blood plasma, reduce cancer embolus generation and tissue fibrosis risk.

In the present invention, the activated complex solution includes metal ion Rb⁺, preferable described Rb⁺From with containing Rubidium mineral matter purification active ionic water or from rich in Rb⁺Plant extracts, the Rb⁺Extract carries for marine alga Take thing.In heretofore described activated complex solution, Rb⁺Concentration is preferably 0.0004~0.0952mg/ml, more preferably For 0.002~0.08mg/ml.Heretofore described Rb⁺It act as and Mg²⁺, Mn²⁺And K⁺Collective effect activates pyruvate kinase (pyruvate kinase, PK), in glycolysis system, it is the enzyme that catalysis forms second ATP reaction.In ATP and Mg²⁺ Under participation, fructose-1, 6-diphosphate kinases 1 (6-phosphofructokinase1, PFK1) is catalyzed 6- phosphoric acid in glycolytic pathway Fructose generation fructose 1,6-diphosphate (Fructosel, 6bisphosphate, F-1,6-BP), accelerates the second of glycolytic pathway Hypophosphorous acidization is reacted, and improves active o content, makes cancer cell that the mechanism of apoptosis occur.

In the present invention, the activated complex solution includes metal ion Li⁺, preferable described Li⁺From with containing Lithium mineral matter purification active ionic water or from rich in Li⁺Plant extracts, the Li⁺Extract is bluish dogbane Wooden tea extraction.In heretofore described activated complex solution, Li⁺Concentration is preferably 0.0004~0.012mg/ml, more Preferably 0.001~0.012mg/ml.Heretofore described Li⁺It act as by supplementing Li⁺Fibrinolysin is activated to discharge with kassinin kinin Enzyme, resolution improve fibrinolytic, reduce fiber protein content in blood plasma, reduce cancer embolus generation and tissue fibrosis risk.

In the present invention, above-mentioned metal ion preferably derives from contains Fe simultaneously²⁺、Ca²⁺、Zn²⁺、Se²⁺、Mg²⁺、Mn²⁺、 Mo²⁺、K⁺、Rb⁺、Li⁺Mineral matter purification active ionic water, the mineral matter comprising above-mentioned metal ion purifies active ion Water preferably entrusts mining company to process, and Qingdao Shen Dongkuang liquid Co., Ltd is entrusted in specific implementation process of the present invention.

The method that the present invention extracts to obtain metal ion to above-mentioned plant source is not particularly limited, and is routinely carried using this area Method is taken, specifically in implementation process of the present invention, entrusts the limited public affairs of Daxing'an Mountainrange Lin Gebei psychrophile science and technology shares Department's processing.

The preparation method of the activated complex is dissolved in for cyanine glucoside extract is mixed with metal ion in the present invention Chelate is formed in water.In activated complex preparation process of the present invention the concentration of anthocyanin and the concentration of metal ion referring to The concentration of anthocyanin and metal ion in above-mentioned activated complex solution, will not be repeated here.

In the present invention, the albumen for p53 gene expressions is distributed mainly on cell caryoplasm, can be with DNA specific bonds, its Activity by phosphorylation, acetylation, methylate, the characteristic such as the posttranslational modification such as ubiquitination regulation and control, from anthocyanin to harmful free radicals Eliminate, participate in the several kinds of mineral elements ion and vitamin confactor Cofacter (s), P53 action targets of enzymic catalytic reaction Matrix metalloproteinase MMP, hypoxia inducible factor HIF, MDM2 zinc finger protein (structure is easily distorted by heavy metal ion), miRNA Nickase Dicer regulation and control are started with, and are proposed that " enclosing target " (Encircle Target) is theoretical and are expressed intervention stratege with P53.The present invention The main biochemical mechanism of action of the activated complex includes：

MiRNA is the endogenic non-coding RNA of organism, and miRNA, which has, suppresses the function that tumour is formed.MiR-34 families Member (including miR-34a and miR-34b/c) is p53 direct action target, and this effect can induce aging, apoptosis and cell Cycle arrest.MiRNA precursors obtain through Dicer cleavages.Dicer is attached to dsRNA, and substantial amounts of cutting mRNA can be triggered anti- Should.Have one group of conservative acid residues sites in each catalytic center of Dicer enzymes, they can combine a magnesium from Son.In Dicer albumen, four conservative amino acid sites in each RNaseIII domain activities site can be with two Individual metal ion (Mg²⁺Or Mn²⁺) be combined, Dicer albumen can utilize " bimetallic ion " mechanism (two-metal- Ionmechanism RNA degradation reactions are catalyzed).

P53 is made sugared in cell by being adjusted to TIGAR (TP53 induces glycolysis and Apoptosis) expression negativity Glycolysis is excessive, the mechanism that intracellular activity oxygen level rises and makes cancer cell that apoptosis occur, by supplementing bivalent metal ion (Mg²⁺ And Mn²⁺) and monovalent metallic ion (K⁺, Rb⁺), activation pyruvate kinase (pyruvate kinase, PK), in glycolysis system In, it is the enzyme that catalysis forms second ATP reaction.In ATP and Mg²⁺Under participation, (the 6- of fructose-1, 6-diphosphate kinases 1 Phosphofructokinase1, PFK1) in glycolytic pathway, catalysis fructose-1, 6-diphosphate generation fructose 1,6-diphosphate (Fructosel, 6bisphosphate, F-1,6-BP), accelerate second of phosphorylation reaction of glycolytic pathway.

One important function mechanism of p53 albumen is by suppressing hypoxia inducible factor (hypoxia inducible Factor, HIF) and VEGF, the formation of fibroblast growth factor, prevent the effect machine of Tumor Angiongesis System.In the case of normoxic, HIF-l α subunits keep relatively low water due to the degradation by Ubiquitin-proteasome It is flat, and in the case of anoxic, the effect of Ubiquitin-proteasome is suppressed, and HIF-l α subunits keep higher level, is gone forward side by side Enter nucleus to be combined with HIF-1 β subunits, form active HIF, activate target gene (such as VEGF, bFGF) downstream, mediate shape Into a series of physiological reaction of adaptation anoxics, promote angiogenesis；When protooncogene activation, p53 albumen can directly with HIF-1 α subunits combine, and cause HIF-1 α albumen to be degraded, so as to inhibit revascularization.

By observing for a long time, entity tumor is mainly in histanoxia area, and many tumor patients show blood red in various degree The symptom of protein decreased, cell oxygen carrying deficiency, HIF activity can be aggravated, promote tumor vascular growth speed.Therefore present invention combination Thing supplements Fe²⁺、Mn²⁺Intake, mainly by supplementing hemoglobin ferrous ion and Intramitochondrial manganese, increase hemoglobin Synthesis, the activity of oxygenase is activated, strengthen blood oxygen concentration.Suppression of the nearly and complementary enhancing p53 to hypoxia inducible factor HIF. The enhancing of oxonium ion, it helps Ubiquitin-proteasome maintains vigour, and makes HIF-l α subunits keep reduced levels.

P53 can activate the prolyl hydroxylase (prolyl hydroxylase, PHDs) of collagen, and the enzyme has anti-blood Pipe formation characteristic, suppress revascularization.The catalytic reaction of prolyl hydroxylase needs Fe²⁺With ascorbate (vitamin C) ginseng With.

Lysyl hydroxylase can make p53 hydroxylatings and prevent its acetylation, suppress its transcriptional activity.Lysine is hydroxylated Enzyme (LOX) is that copper relies on monoamine oxidase, promotes the formation of covalent cross-linking in elastin laminin and collagenous fibres, makes outside tumour cell Matrix, which ossifys, to be hardened, and prevents invasion and attack and DISTANT METASTASES IN of the tumour cell to surrounding tissue.Also there are some researches show LOX high expression It is breast cancer infantile tumour stromal reaction, the LOX of secretion acts on collagen, stimulates tumour cell to stretch pseudopodium projection increase flesh and moves Albumen polymerize, adhesion, improves flesh ball-actin crosslinking, promotes myofilament to shrink, so as to " the high speed as tumor cell migration Highway ".The solution of the present invention is to pass through Mo²⁺Balance and suppression Cu²⁺Activity and absorb, suppress LOX to p53 hydroxyl Change.By supplementing K⁺、Li⁺And Ca²⁺Fibrinolysin and kallikrein are activated, resolution improves fibrinolytic, reduces fiber in blood plasma Protein content, reduce cancer embolus generation and tissue fibrosis risk.

MDM2 oncogenes are combined with p53, can reduce P53 expression.Mdm2 participates in the regulation of p53 negative feedback loops.Increase mdm2 Expression cause p53 exported out of core and the degraded of ubiquinone protein lytic pathway increase.It is can be found that in some p53 positive cancers There is mdm2 to expand and be overexpressed.

MDM2 oncogene fingers --- zinc finger protein, Zn²⁺By Cd²⁺、Hg²⁺、Co²⁺、Cu²⁺Substituted, distort zinc finger Structure, formed such as Cd5Zn2-MT hybrid metal albumen, it is near and heighten MDM2 amplification and overexpression, this also explain heavy metal from Son can cause the carcinogenic principle of gene mutation, can also explain malignant tumour center site Cd²⁺、Hg²⁺Concentration increase, Cu/Zn The reason for ratio dramatically increases compared with normal structure.Zn is added in active compound²⁺、Se²⁺、Mo²⁺, mainly replace and distort zinc finger Cd in protein structure²⁺、Hg²⁺、Co²⁺、Cu²⁺, while suppress Metal Ions Cd²⁺、Hg²⁺、Co²⁺、Cu²⁺Absorption and enzymatic reaction Activity.

The active compound of p53 expression of tumor suppressor gene is improved to a kind of target of the present invention with reference to specific embodiment Thing is further described in detail, and technical scheme includes but is not limited to following examples.

Embodiment 1

It is a kind of to target the activated complex solution for improving p53 expression of tumor suppressor gene, the composition of the activated complex and contain Amount is shown in Table 1.

The targeting of table 1 improves the composition of the activated complex of p53 expression of tumor suppressor gene

Composition	The symbol of element	Per 100ml	Ion concentration (mg/ml)
				Blueberry anthocyanin		300mg	3
Iron	Fe	5mg	0.05
				Calcium	Ca	3mg	0.03
Zinc	Zn	2mg	0.02
				Selenium	Se	10ug	0.0001
Magnesium	Mg	12mg	0.12
				Manganese	Mn	45ug	0.00045
Molybdenum	Mo	10ug	0.0001
				Potassium	K	20mg	0.2
Rubidium	Rb	20ug	0.0002
				Lithium	Li	20ug	0.0002

Wherein blueberry anthocyanin commission Daxing'an Mountainrange Lin Gebei psychrophiles Science and Technology Co., Ltd. processing, the blueberry Anthocyanin is powdered, and wherein the mass content of anthocyanin is 45%.Wherein metal ion derives from contains Fe simultaneously²⁺、Ca²⁺、 Zn²⁺、Se²⁺、Mg²⁺、Mn²⁺、Mo²⁺、K⁺、Rb⁺、Li⁺Mineral matter purification active ionic water, commission Qingdao stretch the eastern limited public affairs of ore deposit liquid It is prepared by department.

The present embodiment in use, blueberry anthocyanin powder is dissolved in mineral matter purification active ionic water, flower Blue or green glycosides forms activated complex with metal ion-chelant.

Embodiment 2

It is a kind of to target the activated complex solution for improving p53 expression of tumor suppressor gene, the composition of the activated complex and contain Amount is shown in Table 2.

The targeting of table 2 improves the composition of the activated complex of p53 expression of tumor suppressor gene

Composition	The symbol of element	Per 100ml	Ion concentration (mg/ml)
				Blueberry anthocyanin		1g	10
Iron	Fe	10mg	0.1
				Calcium	Ca	30mg	0.3
Zinc	Zn	4mg	0.04
				Selenium	Se	100ug	0.001
Magnesium	Mg	25mg	0.25
				Manganese	Mn	50ug	0.0005
Molybdenum	Mo	20ug	0.0002
				Potassium	K	40mg	0.4
Rubidium	Rb	20ug	0.0002
				Lithium	Li	20ug	0.0002

Wherein blueberry anthocyanin commission Daxing'an Mountainrange Lin Gebei psychrophiles Science and Technology Co., Ltd. processing, the blueberry Anthocyanin is powdered, and wherein the mass content of anthocyanin is 30%.Wherein metal ion derives from contains Fe simultaneously²⁺、Ca²⁺、 Zn²⁺、Se²⁺、Mg²⁺、Mn²⁺、Mo²⁺、K⁺、Rb⁺、Li⁺Mineral matter purification active ionic water, commission Qingdao stretch the eastern limited public affairs of ore deposit liquid It is prepared by department.

Embodiment 3

It is a kind of to target the activated complex solution for improving p53 expression of tumor suppressor gene, the composition of the activated complex and contain Amount is shown in Table 3.

The targeting of table 3 improves the composition of the activated complex of p53 expression of tumor suppressor gene

Composition	The symbol of element	Per 100ml	Ion concentration (mg/ml)
				Blueberry anthocyanin		1g	10
Iron	Fe	20mg	0.2
				Calcium	Ca	500mg	5
Zinc	Zn	10mg	0.1
				Selenium	Se	200ug	0.002
Magnesium	Mg	100mg	1
				Manganese	Mn	1mg	0.01
Molybdenum	Mo	200ug	0.002
				Potassium	K	100mg	1
Rubidium	Rb	500ug	0.005
				Lithium	Li	100ug	0.001

Wherein blueberry anthocyanin commission Daxing'an Mountainrange Lin Gebei psychrophiles Science and Technology Co., Ltd. processing, the blueberry Anthocyanin is powdered, and wherein the mass content of anthocyanin is 5%.Wherein metal ion derives from contains Fe simultaneously²⁺、Ca²⁺、 Zn²⁺、Se²⁺、Mg²⁺、Mn²⁺、Mo²⁺、K⁺、Rb⁺、Li⁺Mineral matter purification active ionic water, commission Qingdao stretch the eastern limited public affairs of ore deposit liquid It is prepared by department.

Embodiment 4

Activated complex in embodiment 1 intervenes rehabilitation case.

Mr. Fu, 74 years old, people from Anhui, in August, 2016 was diagnosed as prostate cancer in Anhui hospital of provinces and cities, and PET-CT is shown entirely The multiple Bone tumour of body.Pain is abnormal, inconvenient walking, the movement of roller chair.In August, 2016, through blood test, total prostate specific Antigen has been above 10028.229ng/ml, free prostate gland specificity antigen 28.229ng/ml.Because patient's year gesture is with height, Without more preferable therapeutic scheme, it is proposed that abandon treating, do deathbed care.In Shenzhen, the son of work introduces through friend, agrees to receive The tentative activated complex taken in the embodiment of the present invention 1 of father is allowed to be intervened.Take once a day, each 50ml.Through Spend 15 days and try out, examined again to Fuyang City the People's Hospital, surprisingly find that T-PSA recovers negative, be 0.181.Then, the activated complex 2 months taken in the embodiment of the present invention 1 is held, on January 25th, 2017, is entered in Taihe County Row whole body PEC-CT imaging detections, find brain, eye socket, pharynx nasalis, neck, chest be not apparent from abnormal carbohydrate metabolism increase stove or Obvious enlarged lymph node etc..Prostate without significantly increasing, reduced by Bone tumour site.Most significantly life change is that patient is no longer Wheelchair is relied on, anodyne is eliminated the reliance on, can freely walk, diet is clearly better, and complexion takes a turn for the better, and has rosy cheeks, body weight has increasing.

Embodiment 5

Activated complex in embodiment 2 intervenes rehabilitation case.

Cervical cancer patient Mrs Liang, 40 years old, Cantonese, high-risk HPV virus caused DNA mutation, and 2016 in Shenzhen The cervical carcinoma that South Mountain hospital is diagnosed as, and do Hysterectomy.Feel that somatic reaction is abnormal, goes to Zhongshan University in April, 2017 Attached tumour hospital is diagnosed as cervical cancer relapse, through clinical detection cent lymphocytes 0.591, lymphocyte absolute value 4.1. It is tumor-marker analyte detection, Squamous intraepithelial lesion (SCC) 1.8ng/mL, carcinomebryonic antigen (CEA) 259.28ng/ again afterwards ML, CA125 75.8U/mL.Agree to through patient and family members, sufferers themselves and family members agree to that the present invention is taken in receiving The activated complex of embodiment 2 is intervened, and is taken once a day, each 50ml.After one week, patient substantially feels that action is strong, After 10 days, Shenzhen people's hospital is gone to be detected, Squamous intraepithelial lesion (SCC) reverts to feminine gender, returns to 0.82ng/mL, cent lymphocytes 27.4, lymphocyte absolute value 2.36, revert to normal range (NR).Carcinomebryonic antigen (CEA) 202.9ng/mL is dropped to, CA125 drops to 73.56U/mL.

Embodiment 6

Activated complex in embodiment 3 intervenes rehabilitation case.

Patients with lung cancer Mr. Lei, 58 years old, people from Hunan, on April 17th, 2017 was true by Hunan Bin Zhoushi First People's Hospital Examine as right lung central type carcinoma of lung, with more bilateral rib destructions of bone, consider transfer, part Thoracolumbar disk high density tubercle, transfer is treated Row.Right adrenal gland area low-density shadow, shifts the row for the treatment of.Chemotherapy is simultaneously done by Hou Fu Hong Kong Sanatorium ＆ Hospitals, and PET-CT images are shown, pulmonary carcinosis Become and Bone tumour canceration site is abnormal at totally 15.After receiving chemotherapy through Hong Kong, patient receives in Shenzhen's Luohu Hospital Group's again Medical test, wherein white blood cell count(WBC) are only 1.74, platelet count 120, and neutrophil leucocyte ratio is 39.6, monocyte ratio Value 10.3, neutrophil leucocyte absolute value 0.69, lymphocyte absolute number 0.85.Sufferers themselves and family members agree to that this hair is taken in receiving Activated complex in bright embodiment 3, takes once a day, each 50ml.3 days or so time, patient substantially feel spiritual shape State takes a turn for the better.After 30 days, Luohu Hospital Group's are arrived again and carry out blood testing and CT diagnosis, above dysimmunity index full recovery is Normal range (NR), white blood cell count(WBC) 5.43, platelet count 211, neutrophil leucocyte ratio are 69.1, monocyte ratio 8.8, Neutrophil leucocyte absolute value 3.75, lymphocyte absolute number 1.18.CT images show that right side adrenal area low-density shadow has disappeared Lose.

Activated complex of the present invention passes through from Guangdong, Guangxi, Hong Kong, Anhui, Hunan, the Inner Mongol, Fujian 69 totally The clinic trial intervention of position tumor patient, from anthocyanin harmful free radicals are eliminated, participated in the multi mineral member of enzymic catalytic reaction Plain ion and vitamin confactor (Cofacter (s)), P53 action target matrix metalloproteinases MMP, hypoxia inducible factor The regulation and control of HIF, MDM2 zinc finger protein (structure is easily distorted by heavy metal ion), miRNA nickases Dicer are started with, to P53 genes " enclosing target " (Encircle Target) regulation is carried out, reverses repressed p53 activity in DNA methylation activation tumour cell, with The increase of anthocyanin and composition Mineral Elements concentration and the increase of Time of Administration, p53 protein expressions dramatically increase, P53 gene methylation situations significantly reduce.Compareed by the clinical intervention validity check of Grade A hospital, more than 65 blood samples of patients Critical immune index, tumor markers index are obviously controlled or recover normal completely, there is 4 above the average age for marriage advanced tumor patients, Comparison test index is not obtained.

In summary, activated complex of the present invention improves the active compound of p53 expression of tumor suppressor gene by targetting Thing, more than enough can target and heighten the expression and effect of Suppressor p53, reach control cancer cell development, induction cancer cell aging and Death, so as to realize the treatment to cancer.

Described above is only the preferred embodiment of the present invention, it is noted that for the ordinary skill people of the art For member, under the premise without departing from the principles of the invention, some improvements and modifications can also be made, these improvements and modifications also should It is considered as protection scope of the present invention.

Claims

1. it is a kind of target improve p53 expression of tumor suppressor gene activated complex, it is characterised in that the activated complex by including The raw material chelating of following components obtains：Anthocyanin and metal ion；The metal ion includes Fe²⁺、Ca²⁺、Zn²⁺、Se²⁺、Mg² ⁺、Mn²⁺、Mo²⁺、K⁺、Rb⁺And Li⁺In one or more.

2. a kind of target the activated complex solution for improving p53 expression of tumor suppressor gene, it is characterised in that the activated complex is molten The solvent of liquid is water, and solute includes anthocyanin and metal ion；The metal ion includes Fe²⁺、Ca²⁺、Zn²⁺、Se²⁺、Mg²⁺、 Mn²⁺、Mo²⁺、K⁺、Rb⁺And Li⁺In one or more.

3. activated complex solution according to claim 2, it is characterised in that the anthocyanin is in activated complex solution In concentration be 1~100mg/ml.

4. the activated complex solution according to Claims 2 or 3, it is characterised in that the anthocyanin is spent for plant extract Blue or green glycosides, the plant include purple sweetpotato, grape, blood orange, red cabbage, blueberry, eggplant, cherry, the red certain kind of berries, strawberry, mulberries, hawthorn With the one or more in morning glory.

5. activated complex solution according to claim 4, it is characterised in that anthocyanin in the plant extract anthocyanin Mass content be 3~50%.

6. activated complex solution according to claim 2, it is characterised in that the metal ion is molten in activated complex Concentration in liquid is as follows：Fe²⁺Concentration be 0.1~0.4mg/ml, Ca²⁺Concentration be 0.2~20mg/ml, Zn²⁺Concentration be 0.04~0.38mg/ml, Se²⁺Concentration be 0.0001~0.004mg/ml, Mg²⁺Concentration be 0.4~7mg/ml, Mn²⁺It is dense Spend for 0.0004~0.06mg/ml, Mo²⁺Concentration be 0.0002~0.007mg/ml, K⁺Concentration be 0.4~112.5mg/ Ml, Rb⁺Concentration be 0.0004~0.0952mg/ml, Li⁺Concentration be 0.0004~0.012mg/ml.

7. activated complex solution according to claim 6, it is characterised in that the metal ion is molten in activated complex Concentration in liquid is as follows：Fe²⁺Concentration be 0.2~0.3mg/ml, Ca²⁺Concentration be 0.5~15mg/ml, Zn²⁺Concentration be 0.15~0.28mg/ml, Se²⁺Concentration be 0.0002~0.003mg/ml, Mg²⁺Concentration be 1.5~6mg/ml, Mn²⁺It is dense Spend for 0.01~0.05mg/ml, Mo²⁺Concentration be 0.0008~0.006mg/ml, K⁺Concentration be 5~100mg/ml, Rb⁺'s Concentration is 0.002~0.08mg/ml, Li⁺Concentration be 0.001~0.012mg/ml.

8. activated complex solution according to claim 2, it is characterised in that the metal ion is derived from mineral matter The active ionic water of purification.

9. activated complex solution according to claim 2, it is characterised in that the metal ion derives from and is rich in metal The plant extracts of ion, including Fe²⁺Extract, Ca²⁺Extract, Zn²⁺Extract, Se²⁺Extract, Mg²⁺Extract, Mn²⁺ Extract, Mo²⁺Extract, K⁺Extract, Rb⁺Extract and Li⁺Extract.

10. activated complex solution according to claim 9, it is characterised in that the Fe²⁺Extract extracts for cherry Thing, the Ca²⁺Extract is (0.9~1.1) including mass ratio：(0.9~1.1) Thallus Laminariae (Thallus Eckloniae) extract and Herba Apii graveolentis extract；It is described Zn²⁺Extract includes mass ratio (0.9~1.1)：(0.9~1.1)：The Abelmoschus Esculentus Linn extract of (0.9~1.1), blueberry extract With male silk moth extract；The Se²⁺Extract, Rb⁺Extract is marine algae extract；The Mg²⁺Extract includes mass ratio (0.9~1.1)：(0.9~1.1)：Hazel extract, Semen phaseoli radiati extract and the thyme extract of (0.9~1.1)；The Mn²⁺ Extract includes mass ratio (0.9~1.1)：The Echinacea Purpurea Herb P.E and green-tea extract of (0.9~1.1)；The Mo²⁺Extract For extract of soybean；The K⁺Extract includes mass ratio (0.9~1.1)：(0.9~1.1)：(0.9~1.1)：(0.9~ 1.1) Thallus Laminariae (Thallus Eckloniae) extract, banana extract, peppermint leaf extract and wax gourd extract；The Li⁺Extract is to spread out numbness Tea extraction.